MALE AND FEMALE GENITAL TRACTS AND HIV-1 COMPARTMENTALIZATION IN THE HAART ERA

The drastic reduction, up to undetectability, of blood plasma HIV-1 RNA viral load obtained in most patients after initiation of HAART is accompanied by a parallel reduction of genital fluids’ HIV-1 viral load.⁸,^68-71 A previous study performed in our laboratories showed evidence of HIV-1 replication-competent virus in the semen of patients on HAART, demonstrating its relevance not only in the potential transmission of the disease but also as a viral reservoir.⁸ Moreover, seminal viral load was demonstrated, although at low levels, in the majority of patients on HAART.

This might represent an in vivo reservoir or sanctuary site that may cause reinfection in the peripheral bloodstream and lymphoid tissue, especially when HAART is discontinued, interfering with attempts at viral remission or eradication.

Semen cells are a mixture of spermatozoa, precursors of germ cells, T lymphocytes, macrophages, and epithelial cells. HIV-1 proviral DNA was detected in several of these cell types,⁸,⁷²,⁷³ and cell-free virus can still be detected at very low levels in seminal fluids.⁸,⁶⁹ Of note, there are often significant differences in viral load and viral sequences between semen and peripheral blood, suggesting compartmentalization of HIV-1 replication.⁷⁴,⁷⁵ Recently, subcompartmentalization of HIV-1 quasi-species between seminal plasma and seminal cells was also reported, indicating that HIV-1 in seminal plasma is derived from the prostrate, whereas HIV-1-infected cells in semen originate mostly from the rete testis and epididymis.⁷⁶ These data are further supported by a study by Kiessling and colleagues⁷⁷ that displayed an increase of HIV-1 seminal plasma viral load of 100-fold over that in blood during an episode of prostatitis.

On the other hand, another recent study concluded that seminal fluid mononuclear cells are possible sources for the cell-free virus found in semen, confirming that this remains a controversial issue.⁷⁸ Importantly, these studies were performed on subjects not on HAART. As such, they could not address the possible implications of this compartment as a viral reservoir. The principal types of HIV-1-infected cells in semen are monocytes/macrophages and lymphocytes,⁷³ but the specific individual roles of these two cell types during virally suppressive HAART are not known. The development of viral evolution has to be considered as well as the possibility of reseeding this persistent reservoir either by cell-free virus or by trafficking T cell or monocyte/macrophages. Although the low number of cells and the low seminal viral load make this a very difficult task, characterization of cell-free as well as cell-associated viral strains and tropism is of critical importance in understanding the molecular mechanisms involved in cryptic HIV-1 replication in sanctuaries, where the presence of blood-tissue barriers may reduce the efficacy of HAART.

HIV-1 can also be recovered from vaginal fluids, vaginal cells, and cervical cells.⁷¹’⁷⁹’⁸⁰ Most genital virus arises from the cervix and possibly the upper genital tract. The genital-associated lymphoid tissue, composed of endo- and exocervical stromal lymphocytes, monocytes, and dendritic cells, is considered a potential source of HIV-1 replication.⁷ Furthermore, epithelial cells have been found to be susceptible to HIV-1 infection and replication and to either release HIV particles or transmit virions by cell-to-cell contact.^81,82

A recent study analyzed HIV-1 viral load levels in the cervical-vaginal secretions in 122 HIV-1-infected women using a sensitive technique with a lower detection limit of 80 copies/ml.⁸³ The authors reported that in 40% of women on HAART, cervical vaginal lavages (CVL) samples were positive for the presence of HIV-1 RNA.

Moreover, in 25% of women with undetectable virus in plasma, cervical-vaginal shedding was demonstrated, suggesting not only that blood plasma viral load may fail to predict infectivity of genital secretions but also that there is a possibility of compartmentalization.

The latter finding is in agreement with previous studies in which the higher HIV-1 RNA levels in genital fluid than in blood plasma^70,71,84 and the presence of different drug-selected mutations in distinct compartments, such as blood plasma and endocervix and cervicovaginal secretions, supported this hypothesis.^85,86

The presence of cell-free HIV-1 RNA in cervicovaginal secretions emphasizes the importance of continuing to practice protected sex, even in the era of HAART. Furthermore, the persistence of HIV-1 shedding, even in the presence of HAART, strongly recommends the need for new preventive strategies, such as virucides, in order to block or at least reduce the transmission of HIV-1. The use of microbicides would be paramount, especially in developing countries where sexual transmission plays a major role in the spread of the disease.

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Source: Badley A.D. (ed.). Cell Death During HIV Infection. Taylor & Francis,2006. — 511 p.. 2006

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